Cervical cancer is the second most commonly diagnosed cancer in women worldwide, with ~520, 000 new cases diagnosed every year. High risk human papillomavirus (hrHPVs) have been detected in almost all cervical carcinomas and are thought to be major risk factors for cervical cancer. However, epidemiological studies show that fewer than 4% of women infected with HPV develop invasive cancer. The majority of infected women never develop cancer in their lifetime. Therefore, unknown factors unique to individual hosts appear to contribute to the dysplastic transformation and disease progression. The molecular mechanisms controlling the initiation and progression of cervical cancer are poorly understood. The Hippo pathway has been reported to play critical roles in tumorigenesis in several cancers, including in ovarian cancer. However, the role of the Hippo signaling pathway in the pathogenesis of cervical cancer has not been examined. Our preliminary studies clearly indicate that YAP, the major effector of the Hippo signaling pathway, is overexpressed in cervical cancer and is associated with poor patient survival. Overexpression of wild type YAP or constitutively active YAP promotes proliferation of cervical cancer cells and drives transformation of immortalized cervical epithelial cells. Knockdown of YAP suppressed cervical cancer cell proliferation. Moreover, YAP stimulated growth of human cervical cancer xenografts in athymic nude mice. Intriguingly, we found that the HPV16 E6 protein interacts with YAP to regulate proliferation of cervical cancer cells. We hypothesize that the Hippo pathway plays a central role in the initiation and progression of cervical cancer. In the proposed project, we will systematically examine the role of the Hippo/YAP pathway in the initiation and progression of cervical cancer; determine the potential interaction between the Hippo/YAP pathway and hrHPV oncoproteins using transgenic mouse models, and explore the potential signaling mechanism by which the Hippo pathway interacts with hrHPV oncoproteins to regulate cervical carcinogenesis. Successful achievement of this project will identify the Hippo/YAP pathway as a novel and key regulator of the tumorigenic process in the cervix. These findings will not only significantly expand our knowledge on cervical carcinogenesis, but will also provide new targets for the prevention and treatment of cervical cancer. Moreover, accomplishment of the proposed study will also open new windows for the prevention and treatment of other HPV-associated cancers.